Asthma, a chronic respiratory disease affecting over 20 million Americans and 300 million people worldwide, results from the complex interaction of multiple genetic and environmental factors. Many studies have searched for individual genetic variants that contribute to asthma susceptibility, but a thorough understanding of the genetic basis of asthma has not been achieved. Our main hypothesis is that the genetic architecture underlying asthma susceptibility can be better understood by considering multiple genes and incorporating multiple sources of genomic data, including human asthma and mouse airways hyperresponsiveness (AHR) data. This hypothesis will be addressed via specific aims in which we will: (1) identify genetic variants that predispose humans to asthma and modulate human AHR by mapping regions associated with AHR in inbred strains of mice to human genome-wide association data, (2) use gene expression data, known protein-protein interactions, and known functional pathways to enhance the search for asthma and AHR genetic variants in humans, and (3) integrate individual human genetic variants to create a multivariate predictive model of asthma. Novel variants identified by Specific Aims 1 and 2 will be validated by replication in independent human populations of asthmatics. The predictive model created in Specific Aim 3 will be validated through replication and prediction in independent human populations of asthmatics. By completing the specific aims, we hope to make progress towards the development of a comprehensive model of the genetics of asthma, particularly of asthma characterized by increased airways responsiveness. PUBLIC HEALTH RELEVANCE: By completing this proposal, we hope to identify genetic variants that modulate asthma risk. Identifying such variants could provide biological insights that may eventually lead to a better understanding of asthma. Additionally, we will create a predictive model of asthma, which could potentially lead to the development of a clinical prognostic test of who is at risk for developing asthma.